Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-27
1999-12-21
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 31555
Patent
active
060049537
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the field of biology and medicine, in particular to suppression of the growth of malignant tumors.
The following drugs are known for suppression of tumor growth.
1. Cis-dichlorodiaminoplatinum. Having a wide range of action, it is used for treatment of solid tumors of various localization [1,2], but exhibits high nephrotoxicity [3].
2. Photodynamic therapy of tumors, in which photosensitizers--free tetrapyrrolic macrocyclic ligands or their complexes with metals, e.g. aluminum complex of sulfonated phthalocyanine Al[Pc(SO.sub.3 H).sub.4 ]--are used. Their use is only possible in the case of surface located tumors, more exactly--accessible for a laser probe [4].
3. A drug consisting of a complex of copper (II) with glycylglycylhistidine tripeptide ([Cu(GGH)]Cl) and sodium salt of ascorbic acid in a ratio of 1:10 is the drug most similar to that proposed; it causes an increase in the life-span (ILS) of mice with Ehrlich ascitic carcinoma [5].
Drawbacks of the prototype are low effectiveness related to the low selectivity of that complex in respect of tumors and its instability in physiological conditions, and a high toxicity due to the products of decomposition of the complex.
The object of the present invention is to find more effective and less toxic drugs for suppression of tumor growth.
The essence of the proposed invention is that a drug consisting of a biogenic reductant and a complex of cobalt or iron with substituted phthalocyanines (I) or naphthalocyanines (II) is used to suppress tumor growth. ##STR2## where R.dbd.COONa, SO.sub.3 Na, CH.sub.2 C.sub.5 H.sub.5 N.sup..sym. Cl.sup.-, CH.sub.2 (NH.sub.2).sub.2 S.sup..sym. CCl.sup.-.
The scientific foundation for the invention is literary data on the selective accumulation of tetrapyrrolic macrocyclic compounds and their complexes with metals in tumorous tissues [4, 6] and the facts that we have established which show the high catalytic activity of phthalocyanine complexes of cobalt and iron in model chemical systems, in particular: reductants and analogues thereof, e.g. ascorbic acid, ubiquinone and cysteine; anion-radical of superoxide, hydrogen peroxide and a hydroxyl radical, the cytostatic and other biological activity of which is well known--takes place in this reaction [7]; oxidative degradation of nucleic acids.
METHODS AND RESULTS OF TESTS
Tests of the proposed drug for cytotoxic and antitumor activity were carried out on cultures of tumor cells (in vitro) and on mice with regrafted tumors (in vivo).
DETERMINATION OF THE ACTIVITY OF THE DRUGS ON CULTURES OF TUMOR CELLS (IN
VITRO)
Method 1
The method of evaluation of the cytostatic effect of a combination of phythalocyanines with ascorbic acid in a system in vitro was developed on a culture of tumor cells of human testicular carcinoma (Cao V line).
The culture of cells was grown in a monolayer in medium 199 comprising a 10% solution of an embryonic calf serum.
At the beginning of the experiment the cells were inoculated at a density of 100000/ml in a total volume of 2 ml and incubated at 37.degree. C. for 24 hours. Then the testing was carried out in the following variants:
1. Control
The growth medium for the samples was replaced with a fresh intact nutrient medium and incubated for 48 hours, then .sup.3 H-thymidine (.sup.3 H-T) in a final concentration of 1 .mu.Curie/ml was introduced into the medium of the samples, it was washed with a Hank's solution, a 2.5% solution of perchloric acid, and the acid-insoluble fraction was hydrolyzed in 5 ml of 5% perchloric acid. The hydrolyzates in a volume of 100 .mu.l were transferred into flasks with a scintillation fluid SF-8 and the level of radioactivity in the samples was registered on a RackBeta (Sweden) fluid scintillation counter. The average values of the level of radioactivity were calculated.
2. In order to evaluate the effect of ascorbic acid on the growth of cells of the Cao V line, the growth medium of the samples was replaced with a fresh medium, comprising ascorbic acid in a concentration of 1.times.10.sup.
REFERENCES:
patent: 4393071 (1983-07-01), Fujii et al.
patent: 5358940 (1994-10-01), Capraro et al.
E. Kimoto, Cancer Research 43, pp. 824-828, Feb. 1983, "Enhance-ment of Atumor Activity of Ascorbate against Ehrlich . . . ".
Science, vol. 262, pp. 32-33, Oct. 1993, "Hope for a Magic Bullet That Moves at the Speed of Light".
Aust, Journal of Free Radicals, vol. 1, pp. 3-25, 1985, "Role of Metals in Oxygen Radical Reactions".
Rose, Cancer Treatment Reports vol. 66, No. 1, Jan. 1982, "Anti-tumor Activity and Toxicity of Cisplatin Analogs".
Chissov Valery Ivanovich
Galina, deceased Nikolaevna Novodarova
Gerasimova Galina Konstantinovna
Kalia Oleg Leonidovich
Kazachkina Natalya Ivanovna
Gosudarsvenny Nauchy Tsentr Rossiiskoi Federatsii "Niopik"
Institut Elementoorganicheskikh Soedineny Rossiiskoi Akademii Na
Moskovsky Naucho-Issledovatelsky Onkologichesky Institut
Onkologichesky Nauchy Tsentr Rossiiskoi Akademii Nauk
Travers Russell
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